Salivary cortisol determination in the diagnosis of pediatric Cushing's disease

Endogenous Cushing's syndrome in children is a very rare entity. Diagnosis is complex due to the wide variety of tests available. Recently, the utility of salivary cortisol has been proposed for the diagnosis of this entity, although greater evidence is required, especially in pediatric patients. We report a 14-year-old girl with Cushing's disease due to a pituitary microadenoma in whom salivary cortisol determination was very useful for the diagnosis.     

Diagnosis,treatment and long-term outcome in Cushing's disease

Cushing's disease is uncommon in childhood. It is usually caused by the oversecretion of adrenocorticotrophic hormone (ACTH) by a pituitary corticotroph adenoma. Clinical abnormality is often undetected for long periods of time. The principal clinical features are growth retardation and obesity. We present four patients who were diagnosed with Cushing's disease in a tertiary hospital from January 1995 to December 2002. There were two boys and two girls, aged 10-15 years. The main clinical features at presentation were growth failure and excessive weight gain. The interval between onset of symptoms and diagnosis ranged from 2.5 to 5 years. All patients presented moon face and increased fat around the neck. In all patients, 24-hour urinary free cortisol was high and loss of normal serum cortisol circadian rhythm (3/3) and suppression of cortisol to less than 50 % of the basal level with high-dose but not with low-dose dexamethasone (2/2) were observed. Pituitary microadenoma was detected by magnetic resonance imaging in three patients; no tumor was detected in the fourth patient and inferior petrosal sinus sampling was performed, showing left lateralization of ACTH central secretion. Therapy consisted of transsphenoidal surgery in all patients. Two patients are in remission, one patient presented disease recurrence requiring total hypophysectomy because the tumor could not be completely removed and one patient had persistent disease after a second intervention and required pituitary radiotherapy. Two patients showed pituitary hormone deficiency after therapy.     

TSH-secreting pituitary macroadenoma in an 11-year-old girl

Graves' disease, multinodular toxic goiter or toxic adenoma are the usual causes of hyperthyroidism in children as well as in adults. We report a case of hyperthyroidism due to TSH-secreting pituitary macroadenoma in an 11-year-old girl. The patient was admitted to the Endocrine Department for pituitary function evaluation, five months after transfrontal adenomectomy and pituitary irradiation for a macroadenoma. On admission the patient was clinically hyperthyroid and the work-up established a diagnosis of hyperthyroidism due to TSH-secreting adenoma (high levels of TSH in the face of hyperthyroidism, no TSH response to TRH stimulation, diffuse thyroid goiter without eye signs or pretibial myxedema). Of interest in this case was the fact that: (a) she is the youngest patient reported with hyperthyroidism due to a TSH-secreting macroadenoma and (b) hyperthyroidism was diagnosed after adenomectomy.     

Primary pigmented nodular adrenocortical disease (PPNAD) and pituitary adenoma in a boy with sporadic Carney complex due to a novel, de novo paternal PRKAR1A mutation (R96X)

We report the sporadic case of a 9 year-old boy with Carney syndrome, who presented with precocious puberty due to the endocrinological effects of primary pigmented nodular adrenocortical disease (PPNAD) and a synchronous pituitary adenoma. The adrenal tumor was removed surgically. Following unsuccessful treatment with bromocriptine the pituitary adenoma was also resected and a residual tumor irradiated. Thirty months after diagnosis the boy is free of symptoms. Mutation screening of the entire coding region of the PRKAR1A gene identified five single nucleotide exchanges, four of which were either heterozygous or homozygous polymorphic variants that were also present in his parents. However, the hitherto unreported disease-relevant mutation R96X in exon 3 had occurred de novo on the paternal allele.     

Diagnosis of Cushing's disease in children: A challenge for the radiologist

Cushing's disease is the most common cause of Cushing's syndrome in children and is almost always related to over secretion of ACTH by the pituitary gland. It is important to identify a secreting adenoma prior to surgery. Seven cases studied with MRI are reviewed. In five cases the MRI findings suggested adenoma. Three secreting adenomas were confirmed at surgery. One case was in fact a cyst of the pars intermedia, and nothing could be found in the last case. Two patients presented with apparently normal findings on MRI, which was confirmed. There is a close correlation between identifying an adenoma and the success of surgery.Presented at the 31st Congress of the European Society of Pediatric Radiology, June 1–3, 1994, Brussels, Belgium and selected for publication by an International Group of the ESPR     

ACTH-producing microadenoma of the pituitary in a young female infant with Cushing's disease: report of a case including immunocytologic and ultrastructural studies

A female infant, younger than any other case in the literature, with ACTH-producing microadenoma of the pituitary is reported. She had full-blown symptoms and signs as well as laboratory evidence of Cushing's disease. The tumor was investigated by histology, immunocytology (avidin-biotin-peroxidase complex technique), and electron microscopy. The possibility that the tumor was derived from the fetal intermediate lobe is discussed.     

An adolescent with food-dependent Cushing's syndrome secondary to ectopic expression of GIP receptor in unilateral adrenal adenoma

ACTH-independent Cushing's syndrome may be secondary to the expression of ectopic hormone receptors in adrenal tissue. In food-dependent Cushing's syndrome the adrenals aberrantly express receptors for gastric inhibitory polypeptide (GIP). We present the first case of food- and GIP-dependent adrenal adenoma in an adolescent. A 15 year-old girl presented with signs of hypercortisolism. Urinary cortisol excretion was clearly elevated. Upon the finding of very low fasting plasma cortisol levels with a rise during the morning, food-dependent cortisol secretion was suspected. Hourly measurements of plasma cortisol and GIP levels during a day with and a day without meals showed meal- and GIP-related cortisol secretion. Plasma ACTH levels were undetectable. Abdominal computed tomography showed a tumor of 2.5 x 2.5 x 2 cm in the left adrenal. Unilateral adrenalectomy was performed and microscopic examination of the tumor showed an adrenocortical adenoma. Incubation of adenomatous cells prepared from this tumor with GIP resulted in increased cortisol secretion. Using RT-PCR amplification and cDNA hybridization, the GIP receptor was found to be overexpressed in the adenoma tissue but not in the adjacent adrenal tissue. Twelve months after the operation, hourly measurements of plasma cortisol, GIP and ACTH levels on a day with and a day without meals no longer showed GIP-related cortisol production. The present report shows that in an adolescent with corticotrophin-independent Cushing's syndrome, food-dependent hypercortisolism is a possible diagnosis.     

Cushing's syndrome caused by Ewing's sarcoma secreting corticotropin releasing factor-like peptide.

Procedures were carried out in a 12-year-old girl to relate Ewing's sarcoma of the left tibia with Cushing's syndrome. Computed tomography revealed a normal pituitary and hypothalamus but bilateral adrenal hyperplasia without focal enlargement, thus readily excluding hypothalamic-pituitary-adrenal tumor. Negative results from a high-dose dexamethasone suppression test do not support pituitary-dependent Cushing's disease. Ewing's sarcoma was diagnosed on tibial biopsy. The regression of the physical and biochemical findings of Cushing's syndrome subsequent to amputation of the left lower leg strongly suggests ectopic Cushing's syndrome caused by Ewing's sarcoma. Immunohistochemical studies of the resected bone were negative for corticotropin but positive for corticotropin releasing factor-like peptide. We conclude that this is the first reported case of ectopic Cushing's syndrome in a child that is caused by Ewing's sarcoma secreting corticotropin releasing factor-like peptide.     

Cushing's disease due to a giant pituitary adenoma in early infancy: CT and MRI features

We report the case of a 12-month-old girl presenting with diabetes insipidus and Cushing's disease. Brain magnetic resonance imaging (MRI) demonstrated a large tumour arising from the sella turcica, extending up to the foramen of Monro and invading the cavernous sinuses. Surgery was performed to remove the suprasellar part of the tumour, and histology revealed an adrenocorticotrophin (ACTH) secreting pituitary adenoma. This entity is very rare in this age group and the MRI features have not previously been described.     

Pituitary non-secreting macroadenoma apoplexy in an adolescent. patient report and review of the literature

Pituitary macroadenomas are rare in children and adolescents, and when encountered are usually hormone secreting. Symptomatic pituitary non-secreting macroadenoma apoplexy in an adolescent is rare and potentially life-threatening. A 15 year-old patient is described, hospitalized due to headache, fever and photophobia 4 days prior to admission. A meningeal syndrome was postulated, based on clinical examination and cerebrospinal fluid testing. However, clinical examination and hormone testing revealed partial failure of the anterior pituitary. Computed tomography of the brain demonstrated a space-occupying lesion of the pituitary. Magnetic nuclear resonance imaging suggested the presence of a pituitary macroadenoma. Hypophysectomy was performed. Histological examination revealed an extensive infarction of a pituitary adenoma. Hormonal substitution with thyroxine and corticosteroids was administered. This report emphasizes that pituitary non-secreting macroadenoma apoplexy may rarely be the cause of headache and fever in an adolescent, thus causing difficulties in differential diagnosis from acute meningitis.     

Cushing's syndrome in childhood and adolescence

Objective: To review the diagnosis, management and outcome of Cushing's syndrome in children and adolescents.
Methods: We conducted a retrospective review of nine cases treated between 1976 and 1996 at the Royal Children's Hospital, Melbourne, Australia.
Results: Six children with Cushing's disease and three with primary adrenal disease were identified. Mean age at diagnosis in the Cushing's disease patients was 11.3 years and in the children with primary adrenal disease 9.5 years. The most common presenting symptoms were weight gain and delayed growth. Two children had the unusual presenting symptoms of an eating disorder and hemihypertrophy, respectively. Laboratory diagnosis of Cushing's syndrome was established by demonstration of elevated urine free cortisol, loss of normal diurnal variation of serum cortisol, and loss of suppressibility of cortisol secretion by low dose dexamethasone. Investigations used to determine the aetiology of hypercortisolism included serum adrenocorticotropic hormone (ACTH) levels, high dose dexamethasone suppression tests, imaging studies, and inferior petrosal sinus sampling. Four patients with Cushing's disease had successful transphenoidal adenomectomies. Two patients with bilateral primary pigmented nodular adrenocortical dysplasia underwent bilateral adrenalectomies. One child with an adrenal adenoma was treated by left adrenalectomy.
Conclusions: Cushing's syndrome in children and adolescents remains a diagnostic challenge. Successful treatment often requires the use of multiple tests to achieve the correct diagnosis, appropriate surgery and a good long-term outcome.     

Suppression of Hodgkin's disease in a patient with Cushing's syndrome

Hodgkin's disease, one of the more common tumors in pediatric oncology, has been shown to be highly responsive to steroids in conjunction with other chemotherapy agents. The authors describe a patient with Cushing's syndrome that suppressed his Hodgkin's disease. He developed constitutional symptoms, and his Hodgkin's disease progressed after the removal of his pituitary tumor. The patient is disease-free following ABVD/MOPP chemotherapy. A high level of steroids before treatment, albeit endogenous, did not preclude successful treatment of Hodgkin's disease. The effect of Cushing's syndrome on Hodgkin's disease has not been previously reported.     

Pituitary adenomas in childhood

Pituitary adenomas are common tumors composed of adenohypophysial cells.Although they usually arise in the sella turcica, they may occasionally be ectopic. Pituitary adenomas are rarely diagnosed in. childhood and adolescence, but their mass effect and endocrine abnormalities can compromise both quality and length of life. Many signs or symptoms of pituitary adenoma, complained of in adulthood, not became evident during adolescence, suggesting true prevalence of this tumor in teenagers is higher than expected. Pititury adenoma occuring during adolescence are associated with features or therapeutic needs sometimes different from those occuring in adulthood. At the onset of disease, delay in growth was rarely observed in teenagers with pituitary adenomas. Many girls complain of oligoamenorrhoea and galactorrhoea, while heActache and delay in pubertal development are the most commons features in boys. Hypopituitarism is occasionally encountered in adolescence. Early diagnosis and appropriate choice of therapy are necessary to avoid permanent endocrine complications of disease and its treatment.     

Cushing's disease in an 11-month-old child

Cushing's disease (Pituitary tumor causing bilateral adrenal hyperplasia) is very rare in children and more so in infants. Cushing's syndrome in pediatric patients is usually due to adrenal tumors.We report a case of an 11-month-old child with Cushing's disease caused by a Pituitary macroadenoma.     

Germinoma: a rare cerebral tumor causing central diabetes insipidus in childhood

Germinoma represents 7.8% of cerebral tumors in pediatric age and 50-65% of germ cell cerebral tumors. Generally it is a definite lesion of the pineal gland or suprasellar region, frequently occurring in the first three decades of life. Clinical presentation depends on tumor localization. Pineal lesions generally determine symptoms due to the compression of cerebral structures, causing Parinaud syndrome, while hypothalamic lesions are often characterized by diabetes insipidus, hypopituitarism and visual defects. In the absence of these classic signs and symptoms, however, the diagnosis of germinoma can be difficult. We presented the case of an 8-year-old boy, referred to our clinic for polyuria and polydipsia. Hormonal evaluations demonstrated central diabetes insipidus (CDI), with normal anterior pituitary function. Magnetic resonance imaging (MRI) showed a lack of posterior pituitary gland and partial pituitary stalk enlargement. The patient started therapy with desmopressin (Minirin) with good hydro-electrolytic balance. During follow-up the pituitary function became insufficient with low growth velocity. A second MRI demonstrated a bifocal lesion with dyshomogeneous and cystic appearance, suggesting the diagnosis of germinoma. On the basis of this case report we would like to point out the importance of an early diagnosis in order to improve the prognosis of the disease and the necessity of a careful follow-up of these patients.     

Cushing's syndrome or obesity

A rare case of the Cushing syndrome, due to bilateral adrenal hyperplasia is described. Because of generalized obesity, normal height, normal bone age and family history of obesity, a boy 10 years of age had at first been misdiagnosed as simple obesity. A reduction in height velocity, advancement of bone age and development of precocious pseudopuberty led to a more detailed biochemical investigation and to the correct diagnosis. The clinical picture can be misleading in the differential diagnosis of Cushing's disease versus simple obesity. From a comparison of reports on pediatric Cushing's syndrome, it is obvious that in most pediatric cases fat distribution differs from that of adult Cushing's syndromes. Stunted growth is reported to be more frequent, but normal and excessive height in Cushing's syndrome is not uncommon. In adrenal hyperplasia a retardation of bone age is usually expected. Interpretation of endocrine functions must take into account that simple obesity leads to secondary endocrinopathies, which are similar to the findings in Cushing's syndromes.Plasma cortisol at midnight and 12 hourly excretion of free cortisol in urine as well as overnight Dexamethasone suppression of morning plasma cortisol are judged to be good screning parameters. Plasma ACTH assays can help in the initial diagnosis and are mandatory during the follow up for an early detection of Nelson's syndrome.     

Cushing's disease in children: report of three cases

Cushing's disease is rare in children and adolescents. We report the clinical presentations of three children with Cushing's disease. All three exhibited the typical symptoms and signs of weight gain and growth retardation. Tw o also demonstrated personality changes, hypertension and hypokalemia, the last of these being rarely reported in patients with Cushing's disease. Lack of diurnal changes in serum cortisol levels was the most common biochemical finding. Serum cortisol levels were suppressed by low-dose dexamethasone in one patient, which is not typical for patients with Cushing's disease. Imaging studies are essential for localizing the tumor. Transsphenoidal surgery remains the treatment of choice, and pituitary irradiation should be considered for those patients whose tumors cannot be totally removed. Careful follow-up of these patients with awareness of the possibilities of relapse and the complications of hypopituitarism is indicated.     

McCune-Albright syndrome associated with pituitary microadenoma: patient report

McCune-Albright syndrome (MAS) is a rare disorder characterized by the classic triad of precocious puberty, polyostotic fibrous dysplasia and café-au-lait spots. Additional endocrine abnormalities may also be present, including hyperthyroidism, growth hormone excess and hyperprolactinemia. The most commonly encountered endocrine dysfunction is gonadal hyperfunction. Gonadotropin-independent precocious puberty is typically the initial manifestation of MAS in girls. Ovarian cysts may be detected on pelvic ultrasound. Our patient was also found to have pituitary microadenoma, evidenced by dynamic magnetic resonance imaging.     

Adrenocortical nodular hyperplasia as a cause of Cushing syndrome in the neonatal period]

The case report of a female child born preterm (30th wk of gestation) who developed symptoms of Cushing's syndrome beginning in the neonatal phase is presented. The disease was caused by a unilateral adreno-cortical nodular hyperplasia and was successfully treated by unilateral adrenalectomy. Preoperative treatment with ketoconazole and metyrapone proved to be effective. Symptoms of Cushing's disease including hypertrophic cardiomyopathy were completely reversible within one month after surgery.